Guided Discovery of Antidiabetic Sesquiterpenoids From Lindera Aggregate by Activity Labeled Molecular Networking.

Introduction: The roots of Lindera aggregata (Sims) Kosterm named "Wuyao" in Chinese, showed significant antidiabetic bioactivity detected by the insulin resistance HepG2 cells. However, efficient identification of the new antidiabetic compounds has been lacking.

Objective: To develop a guided discovery strategy for new antidiabetic compounds from L. aggregate with activity labeled molecular networking (ALMN).

Methodology: The constructed ALMN could clearly visualize the activities and the structure nodes, which can facilitate the annotation of the active candidates.

Results: Eight new sesquiterpenoids (1-8) were obtained from the roots of Lindera aggregate according to the ALMN workflow showed antidiabetic activity. As for the new compounds, 1 was characteristic of 15-nor-lindenane type, which was reported for the first time, 2 and 3 of aconitane type, 4 of germarane type, 5-8 of eudesmane type sesquiterpenes.

Conclusion: As results indicated, all the eight compounds showed significant antidiabetic effects, which were consistent with the obtained activity annotations by ALMN. The mechanism of the antidiabetic activity for 1-8 were further delved via Akt/GSK3β signal pathway, which can be observed as potential agents against the insulin resistance for the insulin resistance Type II diabetes.